Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Inhibition of Cytosolic Nucleic Acid Receptor Pathways Using the Small Molecule IKK/TBK1 Kinase Inhibitor MPI-0485520.
Richards, Burt, Zhu, Ju-Fen, Seager, Nathan, Cronin, Monica, Austin, Harry, Douce, Thomas, Cimbora, Daniel
Response to infection by bacterial and viral pathogens includes recognition of foreign nucleic acids. Several cytosolic nucleic acid receptors have been characterized, including the dsRNA receptors MDA5 and RIG-I and the dsDNA receptor DAI. Activation of cytosolic nucleic acid receptors leads to production of type I interferons and proinflammatory proteins through phosphorylation of IRF3 transcription factor by the IKK-related kinase TBK1.
We have developed a small molecule kinase inhibitor, MPI-0485520, that potently and selectively inhibits the IKK-related kinases IKKe and TBK1. MPI-0485520 also exhibits high oral bioavailability, favorable ADME/PK properties, and efficacy in a pharmacodynamic mouse model. To examine cytosolic nucleic acid receptor signaling through IKKe and TBK1, we activated receptors by introduction of dsRNA and dsDNA mimetics into the cytosol of mouse RAW264.7 and human THP-1 monocytic cell lines. Cells were subsequently dosed with MPI-0485520 and mRNA and protein levels of proinflammatory cytokines (IFNa/b, IP-10, IFIT1, MX1, RANTES, and IL-6) were monitored using qRT-PCR and ELISA. Both RAW264.7 and THP-1 cells exhibit robust induction of specific proinflammatory cytokines after cytosolic introduction of the RIG-I and MDA5 agonists, using low and high molecular weight poly(I:C), respectively. This induction was potently inhibited with MPI-0485520 for several of the induced cytokines. Treatment of mouse RAW264.7 cells with the dsDNA receptor agonist poly(dA:dT) also resulted in potent induction of proinflammatory cytokines that was inhibited by MPI-0485520 in a dose-dependent manner. THP-1 cells were not responsive to poly(dA:dT) suggesting that a dsDNA receptor is not present or is poorly induced in this cell line.
In addition to foreign nucleic acids, recent studies have demonstrated that accumulation of endogenous nucleic acids, due to improper disposal of retroelements, can generate a type I interferon response. Patients with mutations in TREX1, RNASEH2A/B/C, or SAMHD1 have a genetic predisposition to autoimmune diseases, including systemic lupus erythematosus, Sjögren's syndrome, and Aicardi-Goutieres syndrome (AGS). Trex1-knockout mouse studies support a model in which accumulated retroelements induce a cytosolic nucleic acid receptor that leads to type I interferon production via an IRF3-dependent pathway. We have demonstrated that production of type I interferons following activation of cytosolic nucleic acid receptors is potently blocked by MPI-0485520. These studies suggest that MPI-0485520 and other IKKe/TBK1 inhibitors may be efficacious in the treatment of forms of lupus, AGS, and Sjögren's syndrome caused by cytosolic nucleic acid receptor activation.
To cite this abstract, please use the following information:
Richards, Burt, Zhu, Ju-Fen, Seager, Nathan, Cronin, Monica, Austin, Harry, Douce, Thomas, et al; Inhibition of Cytosolic Nucleic Acid Receptor Pathways Using the Small Molecule IKK/TBK1 Kinase Inhibitor MPI-0485520. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :493